1. Field of the Invention
The present invention relates to a stable solution of etoposide in 1-methyl-2-pyrrolidinone (henceforth referred to as NMP).
2. Description of the Prior Art
Etoposide is a semi-synthetic product derived from podophyllotoxin. The material is identified by the chemical name 4'-demethylepipodophyllotoxin-9-(4,6-O(R)-ethylidine-.beta.-D-glucopyranos ide). It is approved by the Federal Food and Drug Administration for use in the treatment of refractory testicular cancer and has been proposed for use in the treatment of small cell lung cancer.
Etoposide is currently being marketed under the tradename VePesid as an injection solution containing for each ml, 20 mg of etoposide activity. Before administration by slow intravenous infusion, the solution is diluted with either 0.9% NaCl for Injection, U.S.P. or 5% Dextrose for Injection, U.S.P. to give a final etoposide concentration of 0.2 to 0.4 mg/ml. The diluted solutions are stable for 96 and 48 hrs, respectively (Physician's Desk Reference, Medical Economics Co., 40th Ed., pp. 725-7). Dilution of the commercial formulation by 50 to 100 times requires a large volume of parenteral vehicle and results in prolonged period of drug administration which causes patient inconvenience and discomfort. It is, therefore, desirable to have an etoposide formulation which allows the preparation of an infusion solution of high final etoposide concentration and which is free of etoposide precipitate for a convenient period of time. Such an infusion solution can greatly reduce the time required for drug infusion and represents a benefit to the patients. Japanese Kokai Nos. J60239414 and J60239415 disclose etoposide preparations which are stable against discoloration. European Patent Application No. 193287 discloses etoposide solution containing a water-soluble cellulose ether derivative or polyvinylpyrrolidone.
Etoposide may also be given orally. However, it has been shown that when etoposide is given in a gelatin capsule, a dose twice as high as an IV dose should be given in order to achieve the equivalent blood level (Stewart, D.J., Cancer Treat Rep, 69:269-273, 1985). When a high oral dose is to be given in capsule dosage form, it is desirable to have a concentrated solution of etoposide. Such a concentrated solution will enable the preparation of capsules of smaller sizes thereby allowing for easier ingestion, it may also reduce the number of capsules to be swallowed. The currently marketed etoposide solution having 20 mg/ml etoposide activity may be too dilute for the preparation of a convenient capsule dosage form.
Accordingly, an object of the present invention is to provide a solution of etoposide which upon dilution with a conventional aqueous parenteral vehicle yields a stable solution having a high final etoposide concentration not previously attainable. A further object concerns a concentrated solution of etoposide suitable for encapsulation within a gelatin capsule.